U.S. Pat. No. 4,812,462 describes 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine derivatives as antagonists of angiotensin II (AII) binding at a particular subtype of its cellular receptors, namely the AT.sub.2 receptor. By virtue of their AT.sub.2 receptor antagonist property, these compounds are disclosed to have utility in the treatment of vascular restenosis, atherosclerosis and disorders related to excessive vasopressin (AVP) secretion, various disorders of the central nervous system (CNS), and also have utility in the regulation of female reproductive functions.
Atherosclerotic arterial occlusive disease is a major cause of morbidity and mortality in the United States (W. P. Castelli, Am. J. Med. 76:4-12 (1984)). One important strategy in the treatment of this disorder is the use of various revascularization techniques such as saphenous vein bypass grafting, endarterectomy, and transluminal coronary angioplasty. Unfortunately, the overall success of these revascularization procedures is limited by restenosis due to neointimal hyperplasia. The magnitude of this problem in clinical medicine is increasing with the rising rate of cardiovascular surgery and interventional therapy.
Several factors have been implicated in the pathogenesis of restenosis, including the hormone angiotensin II (Ang II), which is an integral part of the renin-angiotensin system and is a regulator of vascular tone and structure. Ang II is a potent vasoconstrictor which plays a central role in hypertension, congestive heart failure, and vascular diseases. In vivo, Ang II is implicated in the vascular hypertrophy of hypertension since angiotensin converting enzyme (ACE) inhibitors can prevent or attenuate medial hypertrophy in many models of hypertension (G. K. Owens, Hypertension 9:178-187 (1987)). Recently it has been found that inhibitors of ACE and angiotensin II antagonists (AT.sub.1 subtype) will reduce or attenuate the development of intimal hyperplasia in the rat in response to injury (J. S. Powell, et al, Science 245:186-188 (1989); A. W. Clowes, et al, Hypertension 18[Suppl II]): II65-II69 (1991), W. Osterrieder, et al, Hypertension 18 [Suppl II]: II60-II64 (1991)). These growth inhibitory effects are independent of the hemodynamic effects of ACE inhibitors since treatment with other blood pressure lowering drugs does not inhibit this growth (J. S. Powell, et al, J. Card. Pharmacol. 16(Suppl. 4):S42-S 49 (1990)). Similar studies have shown that ACE inhibitors prevent vascular growth in response to injury in guinea pigs (J. P. Clozel, et al, Hypertension 18 [Suppl II]: II55-II59 (1991) and arterial and venous allograft-induced vascular injury in rats (D. Plissonnier, et al, Hypertension 18 [Suppl II]: II47-II54 (1991) and S. P. Roux, et al, Hypertension 18 [Suppl II]:-II43-II46 (1991)). Moreover ACE inhibitors can prevent or attenuate atherosclerosis in Watanabe rabbits (A. V. Chobanian, et al, Clinical Cardiol. 13:43-48 (1990)) and cholesterol fed primates (G. Abers, et al, J. Cardiovascular Pharmacol. 15 (Suppl 5):S56-S72 (1990)).
Angiotensin II has also been shown to play a role in the regulation of vascular smooth muscle cell growth in vitro. In cultured vascular smooth muscle cells, Ang II increases the rates of RNA and protein synthesis and under certain conditions is mitogenic. Moreover, Ang II increases the expression of the proto-oncogenes c-myc, c-jun, and c-fos, as well as growth factors which are involved in Ang II-induced growth, namely, platelet derived growth factor (PDGF), basic fibroblast growth factor, and transforming growth factor-.beta. (TGF-.beta.) (A. J. Naftilan, et al, J. Clin. Invest. 83:1419-1424 (1989)).
The results from multiple laboratories suggest the existence of receptor isoforms which possess different binding properties and different intracellular signals. Recently, two classes of receptor antagonists have been used to classify these receptors (A. T. Chiu, et al, Biochem. Biophys. Res. Comm. 165:196-203 (1989)). The AT-1 receptors, present on multiple cell types, appear to be coupled via G proteins to phospholipase C. AT-1 receptors are known to be selectively antagonized by Dup753 (A. T. Chiu, et al, Biochem. Biophys. Res. Comm. 172:1195-1202 (1990); D. T. Dudley, et al, Mol. Pharmacol. 38:370-377 (1990)). Stimulation of this receptor leads to inositol metabolism, increases in intracellular calcium, and activation of protein kinase C. Thus, The AT-1 receptor is the classical membrane Ang II receptor. Blockade of these receptors has been shown to inhibit induced vascular growth. It has been shown that AT-1 receptor antagonists also reduce or attenuate the development of intimal hyperplasia in the rat in response to injury (M. F. Prescott, et al, American Journal of Pathology 139:1291-1296 (1991); R. F. Kauffman, et al, Life Sciences 49:PL-223-PL-228 (1991), and H. Azuma, et al, Br. J. Pharmacol. (1991)).
A second Ang II receptor subtype, AT-2, has been recently discovered and this receptor has a more limited distribution and may not be coupled to G proteins. This receptor has been found to selectively bind compounds utilized in the present invention. The physiologic role of the AT.sub.2 receptor has been speculated as mediator of the growth potentiation effects of Ang II. This is based on the observation that this receptor subtype is expressed during fetal development (E. F. Grady, et al, J. Clin. Invest. 88:921-933 (1991)). Viswanathan, et al (Biochem. Biophys. Res. Comm. 179:1361-1367 (1991)) reported that AT-2 receptors are the predominant isoform in the neonatal vasculature but are only a minor component in that of the adult. The mechanism of action of the compounds utilized in the present invention pertains to their binding to the AT-2 receptors found in proliferating vascular smooth muscle.
The present invention is also related to the discovery that the AT.sub.2 receptor is found in the central nervous system (CNS) of mammals, and that compounds of general Formula I described herein are effective in blocking angiotensin II binding at AT.sub.2 receptors in various brain regions. Angiotensin II is known to modulate CNS nerve sensitivity to neurotransmitters such as catecholamines, serotonin, and enkephalins, and additionally, angiotensin II is a neurotransmitter that regulates the release of hormones from the brain (Phillips, Ann. Rev. Physiol. 49:413-35 (1987)). Agents that block the activity of angiotensin II at AT.sub.2 receptors in the CNS will ameliorate disorders associated with abnormal nerve activity and abnormal hormone secretion related to exaggerated AT.sub.2 mediated responses to angiotensin II. The compounds of general Formula I, being AT.sub.2 antagonists, have possible utility in the treatment and diagnosis of numerous neurological, psychiatric, neuroendocrine, neurodegenerative, and neuroimmunological disorders including, but not limited to, those associated with addiction, anxiety, depression, epilepsy, hyperactivity, memory, pain, Parkinsonism, psychosis, regulation of autonomic functions, sleep, and tardive dyskinesia.
Barnes, et al, in Brain Research 507: 341-343 (1990), describe the effects of angiotensin II as an inhibitor of potassium-stimulated release of ACh from human temporal cortex, giving rise to elevated levels of ACh in cortical tissue. Rats treated with an angiotensin converting enzyme (ACE) inhibitor, a drug that blocks the formation of angiotensin II, show reductions in striatal ACh. ACE inhibitors have been shown to enhance cognitive performance in rodent tests of cognition by Costall, et al, in Pharmacol. Biochem. & Behavior 33:573-579 (1989).
Since both ACE inhibitors and angiotensin receptor antagonists block the actions of angiotensin II in the brain, it is reasonable that both will enhance cognitive performance.
Another known CNS effect of angiotensin II is stimulation of the release of pituitary and hypothalamic hormones including vasopressin (AVP), oxytocin, adrenocorticotrophic hormone (ACTH), prolactin, and luteinizing hormone (LH). Thus, compounds of general Formula I have utility in treatment of various neuroendocrine disorders that are dependent upon the release of hormones resulting from angiotensin II stimulation of AT.sub.2 receptors.
Vasopressin (AVP), also known as antidiuretic hormone, is a peptide hormone which causes decreased urinary output, increased urine density, and reduced thirst. In normal physiology, it is important for conservation of body fluid. Schiavone, et al, in Hypertension 17:425 (1991), describe the effects of AT.sub.2 antagonists, in antagonizing the angiotensin II-induced secretion of AVP from isolated rat hypothalamo-neurohypophysial explants. Excessive secretion of AVP has been linked to a number of disorders including excessive water retention associated with the female reproductive disorder known as premenstrual syndrome (PMS) (Janowski, et al, Psychosomatic Medicine 35:143-154 (1973)) and impaired water excretion with adrenal insufficiency. It has also been linked to Schwartz-Bartter syndrome (an AVP secreting brain tumor), congestive heart failure, liver cirrhosis, nephrotic syndromes, central nervous injuries, acute psychotic states, lung disease, dysmenorrheic uterine hyperactivity, and premature labor (Laszlo, et al, ibid.). Compounds of general Formula I, by virtue of their ability to block angiotensin II-induced AVP secretion, have utility in treatment of the above disorders.
The present invention is also related to the discovery that AT.sub.2 receptors are found in female reproductive organs of mammals including uterus (Data in Table 1, hereof and in Dudley, et al, ibid.) and ovaries. The role of angiotensin II in processes leading to ovulation has been reviewed by Andrade-Gordon, et al, in Biochemical Pharmacology 42:715-719 (1991). Compounds of general Formula I inhibit the binding of angiotensin II to AT.sub.2 receptors in reproductive tissues, including uterus and ovarian follicles and hence antagonize the effects of angiotensin II therein.
AT.sub.2 receptor antagonists thus have potential utilities in the regulation of fertility and the menstrual cycle.